Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives

ABSTRACT

The present invention provides (i) a process for preparing a 2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivative, (ii) conversion of the lactone to nucleosides with potent anti-HCV activity, and their analogues, and (iii) a method to prepare the anti-HCV nucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 11/185,988, entitled “PREPARATION OF ALKYL-SUBSTITUTED2-DEOXY-2-FLUORO-D-RIBOFURANOSYL PYRIMIDINES AND PURINES AND THEIRDERIVATIVES,” filed on Jul. 21, 2005 now abandoned and assigned to thesame assignee as this application. The aforementioned patent applicationis expressly incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides (i) a process for preparing a2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivative, (ii) conversion ofthe lactone to nucleosides with potent anti-HCV activity, and theiranalogues, and (iii) a method to prepare the anti-HCV nucleosidescontaining the 2′-deoxy-2′-fluoro-2′-C-methyl-β-D-ribofuranosylnucleosides from a preformed, preferably naturally-occurring,nucleoside.

BACKGROUND OF THE INVENTION

In light of the fact that HCV infection has reached epidemic levelsworldwide, and has tragic effects on the infected patients. Presentlythere is no universally effective treatment for this infection and theonly drugs available for treatment of chronic hepatitis C are variousforms of alpha interferon (IFN-α), either alone or in combination withribavirin. However, the therapeutic value of these treatments has beencompromised largely due to adverse effects, which highlights the needfor development of additional options for treatment.

HCV is a small, enveloped virus in the Flaviviridae family, with apositive single-stranded RNA genome of ˜9.6 kb within the nucleocapsid.The genome contains a single open reading frame (ORF) encoding apolyprotein of just over 3,000 amino acids, which is cleaved to generatethe mature structural and nonstructural viral proteins. ORF is flankedby 5′ and 3′ non-translated regions (NTRs) of a few hundred nucleotidesin length, which are important for RNA translation and replication. Thetranslated polyprotein contains the structural core (C) and envelopeproteins (E1, E2, p7) at the N-terminus, followed by the nonstructuralproteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The mature structuralproteins are generated via cleavage by the host signal peptidase. Thejunction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3protease, while the remaining four junctions are cleaved by theN-terminal serine protease domain of NS3 complexed with NS4A. The NS3protein also contains the NTP-dependent helicase activity which unwindsduplex RNA during replication. The NS5B protein possesses RNA-dependentRNA polymerase (RDRP) activity, which is essential for viralreplication. It is emphasized here that, unlike HBV or HIV, no DNA isinvolved in the replication of HCV.

U.S. patent application (Ser. No. 10/828,753) discloses that1-(2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl)cytosine (14) is apotent and selective anti-HCV agent. The original synthetic procedures(Schemes 1-3) are quite inefficient, with overall yields at or below 4%and are not amenable to large-scale.

What is needed is a novel and cost effective process for the synthesisof 2-C-alkyl-2-deoxy-2-substituted-D-ribopyranosyl nucleosides that haveactivity against HCV.

SUMMARY OF INVENTION

The present invention as disclosed herein relates to the composition andsynthetic methods of compounds of general formulas [I] and [II],

wherein

-   -   X is halogen (F, Cl, Br),    -   Y is N or CH,    -   Z is, halogen, OH, OR′, SH, SR′, NH₂, NHR′, or R′    -   R^(2′) is alkyl of C₁-C₃, vinyl, or ethynyl;    -   R^(3′) and R^(5′) can be same or different H, alkyl, aralkyl,        acyl, cyclic acetal such as 2′,3′-O-isopropylidene or        2′,3-O-benzylidene, or 2′,3′-cyclic carbonate;    -   R², R⁴, and R⁵ are independently H, halogen including F, Cl, Br,        I, OH, OR′, SH, SR′, N₃, NH₂, NHR′, NR′₂, NHC(O)OR′, lower alkyl        of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such        as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═CH₂,        halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as        CH═CHCl, CH═CHBr and CH═CHI, lower alkynyl of C₂-C₆ such as        C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, hydroxy        lower alkyl of C₁-C₆ such as CH₂OH and CH₂CH₂OH, halogenated (F,        Cl, Br, I) lower alkyl of C₁-C₆, lower alkoxy of C₁-C₆ such as        methoxy and ethoxy, CO₂H, CO₂R′. CONH₂, CONHR′, CONR′₂,        CH═CHCO₂H, CH═CHCO₂R′; and,    -   R′ is an optionally substituted alkyl of C₁-C₁₂ (particularly        when the alkyl is an amino acid residue), cycloalkyl, optionally        substituted alkynyl of C₂-C₆, optionally substituted lower        alkenyl of C₂-C₆, or optionally substituted acyl.

In other aspects, the present invention provides methods to preparenucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosylmoiety of general structures of III and IV,

through (i) synthesis of the 3,5-protected2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone intermediate of generalstructure V, (ii) conversion of V into purine and pyrimidine nucleosidesof general structures of III and IV, and (iii) preparation ofnucleosides of general structures of III and IV from preformed,preferably natural, nucleosides.

Regarding III, IV and V above, R⁴ and R⁵ are as defined above and R³ andR⁵ can be independently H, Me, Acyl (such as Ac, Bz, substituted Bz),benzyl, substituted benzyl, Trityl, Trialkylsilyl, t-Butyldialkylsilyl,t-Butyldiphenylsilyl, TIPDS, THP, MOM, MEM, or R³ and R⁵ are linkedthrough —SiR₂—O—SiR₂— or —SiR₂—, wherein R is a lower alkyl group suchas Me, Et, n-Pr or i-Pr.

Still another aspect of the present invention are the novel lactoneintermediates of formula V and processes for the preparation of thelactone intermediates as detailed below, including precursor esterintermediates as also detailed below.

DETAILED DESCRIPTION

Presently no preventive means against Flaviviridae, including hepatitisC virus (HCV), Dengue virus (DENV), West Nile virus (WNV) or YellowFever virus (YFV), infection is available. The only approved therapiesare for treatment of HCV infection with alpha interferon alone or incombination with the nucleoside ribavirin, but the therapeutic value ofthese treatments has been compromised largely due to adverse effects. Itwas recently discovered that a group of nucleosides, including2′-deoxy-2′-fluoro-2′-C-methylcytidine (14), exhibit potent andselective activity against replication of HCV in a replicon system.However, the difficulty of chemical synthesis of this and analogousnucleosides impedes further biophysical, biochemical, pharmacologicalevaluations mandatory for development of clinical drugs for treatment ofFlaviviridae infection.

The present invention provides an efficient preparation of nucleosidescontaining the 2-deoxy-2-fluoro-2-C-methyl-D-ribofuranosyl moiety IIIand IV, through (i) synthesis of intermediate the 3,5-protected2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone of general structure V,(ii) conversion of V into purine and pyrimidine nucleosides of generalstructures of III and IV, and (iii) preparation of nucleosides ofgeneral structures of III and IV from preformed, preferably natural,nucleosides.

DEFINITIONS

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication. Thus, in a compound such as R^(a)XYR^(a), wherein R^(a) is“independently carbon or nitrogen”, both R^(a) can be carbon, both R^(a)can be nitrogen, or one R^(a) can be carbon and the other R^(a)nitrogen.

As used herein, the terms “enantiomerically pure” or “enantiomericallyenriched” refers to a nucleoside composition that comprises at leastapproximately 95%, and preferably approximately 97%, 98%, 99% or 100% ofa single enantiomer of that nucleoside.

As used herein, the term “substantially free of” or “substantially inthe absence of” refers to a nucleoside composition that includes atleast 85 or 90% by weight, preferably 95% to 98% by weight, and evenmore preferably 99% to 100% by weight, of the designated enantiomer ofthat nucleoside. In a preferred embodiment, in the methods and compoundsof this invention, the compounds are substantially free of enantiomers.

The term “alkyl,” as used herein, unless otherwise specified, refers toa saturated straight or branched hydrocarbon chain of typically C₁ toC₁₀, and specifically includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl, and the like. The term includes both substituted andunsubstituted alkyl groups. Alkyl groups can be optionally substitutedwith one or more moieties selected from the group consisting ofhydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. Oneor more of the hydrogen atoms attached to carbon atom on alkyl may bereplaces by one or more halogen atoms, e.g. fluorine or chlorine orboth, such as trifluoromethyl, difluoromethyl, fluorochloromethyl, andthe like. The hydrocarbon chain may also be interrupted by a heteroatom,such as N, O or S.

The term “lower alkyl,” as used herein, and unless otherwise specified,refers to a C₁ to C₄ saturated straight or branched alkyl group,including both substituted and unsubstituted forms as defined above.Unless otherwise specifically stated in this application, when alkyl isa suitable moiety, lower alkyl is preferred. Similarly, when alkyl orlower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl ispreferred.

The term “cycloalkyl”, as used herein, unless otherwise specified,refers to a saturated hydrocarbon ring having 3-8 carbon atoms,preferably, 3-6 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. The cycloalkyl group may also be substitutedon the ring by and alkyl group, such as cyclopropylmethyl and the like.

The terms “alkylamino” or “arylamino” refer to an amino group that hasone or two alkyl or aryl substituents, respectively.

The term “protected,” as used herein and unless otherwise defined,refers to a group that is added to an oxygen, nitrogen, or phosphorusatom to prevent its further reaction or for other purposes. A widevariety of oxygen and nitrogen protecting groups are known to thoseskilled in the art of organic synthesis. Non-limiting examples include:C(O)-alkyl, C(O)Ph, C(O)aryl, CH₃, CH₂-alkyl, CH₂-alkenyl, CH₂Ph,CH₂-aryl, CH₂O-alkyl, CH₂O-aryl, SO₂-alkyl, SO₂-aryl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

The term “aryl,” as used herein, and unless otherwise specified, refersto phenyl, biphenyl, or naphthyl, and preferably phenyl. The termincludes both substituted and unsubstituted moieties. The aryl group canbe substituted with one or more substituents, including, but not limitedto hydroxyl, halo, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in T. W. Greene and P.G. M. Wuts, “Protective Groups in Organic Synthesis,” 3rd ed., JohnWiley & Sons, 1999.

The terms “alkaryl” or “alkylaryl” refer to an alkyl group with an arylsubstituent. The terms “aralkyl” or “arylalkyl” refer to an aryl groupwith an alkyl substituent, as for example, benzyl.

The term “halo,” as used herein, includes chloro, bromo, iodo andfluoro.

The term “acyl ester” or “O-linked ester” refers to a carboxylic acidester of the formula C(O)R′ in which the non-carbonyl moiety of theester group, R′, is a straight or branched alkyl, or cycloalkyl or loweralkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl,aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionallysubstituted with halogen (F, Cl, Br, I), C₁ to C₄ alkyl or C₁ to C₄alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl includingmethanesulfonyl, the mono, di or triphosphate ester, trityl ormonomethoxytrityl, substituted benzyl, trialkylsilyl (e.g.dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the estersoptimally include a phenyl group.

The term “acyl” refers to a group of the formula R″C(O)—, wherein R″ isa straight or branched alkyl, or cycloalkyl, amino acid, aryl includingphenyl, alkylaryl, aralkyl including benzyl, alkoxyalkyl includingmethoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl(including lower alkyl), aryl including phenyl optionally substitutedwith chloro, bromo, fluoro, iodo, C₁ to C₄ alkyl or C₁ to C₄ alkoxy,sulfonate esters such as alkyl or aralkyl sulphonyl includingmethanesulfonyl, the mono, di or triphosphate ester, trityl ormonomethoxy-trityl, substituted benzyl, alkaryl, aralkyl includingbenzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such asphenoxymethyl. Aryl groups in the esters optimally comprise a phenylgroup. In particular, acyl groups include acetyl, trifluoroacetyl,methylacetyl, cyclopropylacetyl, cyclopropyl carboxy, propionyl,butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl,2-acetoxy-2-phenylacetyl, diphenylacetyl,α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl,2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl,2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl,chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl,bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl,chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl,tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl,7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl,7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl,7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl,7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl,nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl,methyl 3-amino-5-phenylthiophene-2-carboxyl,3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl,2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl,stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl,pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl,2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl,perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolylcarbonyl, perfluorocyclohexyl carboxyl, crotonyl,1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,1-pyrrolidinecarbonyl, 4-phenylbenzoyl. When the term acyl is used, itis meant to be a specific and independent disclosure of acetyl,trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl,hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl,diphenylacetyl, ct-trifluoromethyl-phenylacetyl, bromoacetyl,4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl,2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl,perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl,tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl,methoxybenzoyl, 2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearyl,3-cyclopentyl-propionyl, 1-benzene-carboxyl, pivaloyl acetyl,1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl,cyclopropane-carboxyl, cyclobutane-carboxyl, 4-methylbenzoyl, crotonyl,1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,4-phenylbenzoyl.

The term “lower acyl” refers to an acyl group in which R″, abovedefined, is lower alkyl.

The term “purine” or “pyrimidine” base includes, but is not limited to,adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl,aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-allcylaminopurine, N⁶-thioallcyl purine, N²-alkylpurines,N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines,C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine,C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine,C⁵-iodopyrimidine, C⁶-Iodo-pyrimidine, C⁵—Br-vinyl pyrimidine,C⁶—Br-vinyl pyriniidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine,N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, andpyrazolopyrimidinyl. Purine bases include, but are not limited to,guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.Functional oxygen and nitrogen groups on the base can be protected asnecessary or desired. Suitable protecting groups are well known to thoseskilled in the art, and include trimethylsilyl, dimethylhexylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups,and acyl groups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl.

The term “amino acid” includes naturally occurring and synthetic α, β, γor δ amino acids, and includes but is not limited to, amino acids foundin proteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In a preferred embodiment, the amino acid is inthe L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl,β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl orβ-histidinyl. When the term amino acid is used, it is considered to be aspecific and independent disclosure of each of the esters of α, β γ or δglycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tryptophan, proline, serine, threonine, cysteine,tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginineand histidine in the D and L-configurations.

The term “pharmaceutically acceptable salt or prodrug” is usedthroughout the specification to describe any pharmaceutically acceptableform (such as an ester, phosphate ester, salt of an ester or a relatedgroup) of a compound which, upon administration to a patient, providesthe active compound. Pharmaceutically acceptable salts include thosederived from pharmaceutically acceptable inorganic or organic bases andacids. Suitable salts include those derived from alkali metals such aspotassium and sodium, alkaline earth metals such as calcium andmagnesium, among numerous other acids well known in the pharmaceuticalart. Pharmaceutically acceptable salts may also be acid addition saltswhen formed with a nitrogen atom. Such salts are derived frompharmaceutically acceptable inorganic or organic acids, such ashydrochloric, sulfuric, phosphoric, acetic, citric, tartaric, and thelike. Pharmaceutically acceptable prodrugs refer to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host to form thecompound of the present invention. Typical examples of prodrugs includecompounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound.

Preparation of the Compounds (i) Synthesis of3,5-Di-O-protected-D-ribono-γ-lactone

Wittig reaction of 2,3-O-isopropylidene-D-glyceraldehyde 39 (Scheme 4)with commercially available 40 affords the (E)-product 41 as a majorproduct. Sharpless dihydroxylation (J. Org. Chem. 1992, 57, 2768-2771)using AD-mix-β as a dihydroxylation reagent gives only the desiredproduct 42 in very high yield. High yield lactonization of 42 to2-C-methyl-D-arabino-γ-lactone (46) is achieved by HCl/MeOH treatment.Selective O-benzoylation of primary and secondary OH groups yields3,5-di-O-benzol derivative 47 in high yield. Treatment of 47 with DASTor Deoxofluor, [bis(2-methoxyethyl)amino]sulfur trifluoride, undervarious conditions gives trace amounts of the desired2′-fluoro-ribono-γ-lactone 49, but mostly a mixture from which thenon-fluorinated ribonolactone (48) is isolated. However, treatment of 47with excess, preferably three (3) equivalents, of tertiary amine,preferably diisopropylethylamine, and excess, preferably five (5)equivalents, of DAST or Deoxofluor provides 49 in ˜50% yield. It wasalso found that using 3,5-O-MOM instead of benzoyl protection, the yieldof 48 approaches 90%. Thus, treatment of 46 with dimethoxymethane in thepresence of strong acid such as trifluoromethylsulfonic acid affords 50,which upon reaction with DAST or Deoxofluor in the presence of baseyielded 87% isolated yield of 49.

It was also discovered that smooth fluorination can occur upon treatmentof the open-chain monobenzoate 43, which can be readily obtained byselective benzoylation of 42, with DAST or Deoxofluor giving rise to thedesired ethyl2-deoxy-2-fluoro-2-C-methyl-3-O-benzoyl-4,5-O-isopropylidene-D-ribonate44. Lactonization of 44 gives only the γ-lactone 45. Furtherbenzoylation of 45 affords dibenzoate 49.

In one embodiment of the present invention, a method is provided for thesynthesis of intermediate 49 through Reformatsky condensation of 39 withan alkyl 2-bromopropionate such as 53 (Scheme 5) in the presence ofactivated zinc in an ethereal solvent such as diethyl ether ortetrahydrofuran (or a mixture of the two solvents) to give 54, which isconverted to 55 by oxidation. Possible oxidizing agents are: activateddimethylsulfoxide, such as a mixture of dimethylsulfoxide,trifluoroacetic anhydride or acetic anhydride (a Swern/Moffatoxidation); chromium trioxide or other chromate reagent; Dess-Martinperiodinane; or tetrapropylammonium perruthenate (TPAP) with or withoutmolecular sieves. This oxidation to provide the C-3 ketone preferablyproceeds without affecting the stereochemistry at C-4.

Fluorination of 55 is performed at the 2-position using an electrophilicfluorination (“F⁺”) in an appropriate solvent such as dimethylformamide,tetrahydrofuran, ethanol, tert-butanol, or diethyl ether or anycombination of these solvents known to those skilled in the art (Rozen,et. al., J. Org. Chem., 2001, 66, 7646-7468; Jun-An Ma and DominiqueCahard, Journal of Fluorine Chemistry, 2004, in press, and referencescited therein), to afford 56. Some non-limiting examples ofelectrophilic fluorinating reagents are Selectflour®,N-fluorosulfonimide (NFSI), and AcOF. Stereoselective fluorination canbe achieved by using a catalyst such as an asymmetric transition metalcomplex catalyst as taught by Sodeoka, et al. (JP2004010555) or by othercatalysts. The starting β-keto ester 55 may also be first converted to aketene silyl acetal prior to fluorination (Rozen, et. al., J Org. Chem.,2001, 66, 7646-7468).

Selective reduction of the C-3 ketone 56 using triphenylsilane in thepresence of a Lewis acid such as AlCl₃ or in the presence of an organicacid such as trifluoroacetic acid (Kitazume, et al., J. Org. Chem.,1987, 52, 3218-3223) provides two 2,3 anti products 57 and 58. However,by utilizing a stereoselective fluorination combined with the selectivereduction, a good yield (with high diastereomeric excess) of 58 can beachieved. Benzoylation of 58 gives 44 which is converted to lactone 45as described earlier.

(ii) Preparation of Nucleosides Containing2-deoxy-2-fluoro-3-methyl-D-ribofuranosyl Moiety by Condensation

A lactone such as 49 can be reduced to the corresponding lactol withDIBAL-H. After acetylation of the anomeric hydroxyl group, 59 (Scheme 6)is obtained in high yield. Condensation of 59 with silylated base (e.g.,silylated N⁴-benzoylcytosine under Vorbrüggen's conditions) affords amixture of protected anomeric nucleosides 60 and 60-α. After separationof the anomers, the desired β-nucleoside 14 is prepared by deprotectionwith metal alcoholate in alcohol, preferably NaOMe/MeOH, or methanolicammonia.

Compound 59 can be converted into the bromo sugar 61, (Scheme 7) whichis condensed with a sodium salt of purine, e.g., sodio-N6-benzoyladenineto give the corresponding protected purine nucleoside 62. The desiredfree nucleoside 63 is readily obtainable by saponification.

(iii) Synthesis from Preformed Nucleosides

Using preformed nucleosides as starting materials for preparation of thedesired 2′-C-alkyl-2′-deoxy-2′-fluoro-β-D-ribonucleosides has certainadvantages, as the formation of anomers and their subsequent separationcan be circumvented, resulting in high yields of the targetednucleosides.

Two procedures to prepare the desired nucleoside 14 from nucleosidestarting materials have been disclosed (Schemes 2 and 3). As mentionedearlier, however, these procedures also produced two undesirableproducts 22 and 23, the latter produced by neighboring groupparticipation as shown in Scheme 8. The separation of the desirednucleoside 14 from the mixture is rather cumbersome. Thus, thisinvention prevents production of 23 using non-participating protectinggroup, such as THP, methyl, ethyl, benzyl, p-methoxybenzyl-,benzyloxymethyl, phenoxymethyl, methoxymethyl, ethoxymethyl, mesyl,tosyl, trifluoroacetyl, trichloroacetyl, at the 3′-OH group.

An example is shown in Scheme 9. WhenN⁴,5′-O-dibenzoyl-3′-O-mesyl-2′-deoxy-2′-C-methyl-β-D-arabinofuranosylcytosine(64) is treated with DAST or Deoxofluor, the desired fluorinated product65 is obtained in 54% yield along with the olefin 66 in 39% yield. Asexpected, no unfluorinated cytidine derivative 67 is formed indetectable amounts. There are several ways to de-protect 65 to 14. Anexample is shown in Scheme 9 that requires a double inversion of the3′-configuration.

When the 3′-O-substituent is a non-participating and non-leaving group,such as methoxymethyl (MOM), methyl, benzyl, methoxybenzyl ortetrahydropyranyl, the intermediate is fluorinated more effectively than64.

The following examples are presented to illustrate the present inventionbut are not to be limited thereto.

Experimental: 2,3-O-Isopropylidene-D-glyceraldehyde (39) is prepared byliterature procedures (Organic Synthesis, Annual Volume 72, page 6; J.Org. Chem. 1991, 56, 4056-4058) starting from commercially availableprotected D-mannitol. Other reagents, including 40 and AD-mix-β, arefrom commercial sources.

EXAMPLES Example 1 Ethyltrans-2,3-dideoxy-4,5-O-isopropylidene-2-C-methyl-D-glycero-pent-2-enonate(41)

To a solution of (carbethoxyethylidene)triphenylphosphorane (40, 25 g,69 mmol) in dry CH₂Cl₂ (65 mL) at room temperature is added dropwise asolution of 2,3-O-isopropylidene-D-glyceraldehyde (39, 9.41 g, 72.3mmol) in CH₂Cl₂ (30 mL). The mixture is stirred at room temperatureovernight. The reaction mixture is then concentrated to dryness, dilutedwith light petroleum ether (300 mL), and kept at room temperature for 2h. Triphenylphosphine oxide precipitated is removed by filtration and analiquot is concentrated in vacuo. The residue is purified by silica gelcolumn chromatography with 0-1.5% EtOAc in hexanes to give 41 (10.4 g,71%) as an oil (Carbohydrate Res., 115, 250-253 (1983)). ¹H NMR (CDCl₃)δ 1.30 (t, J=6.8 Hz, 3H, —OCH₂ CH₃ , 1.41 (, s, 3H, CH₃), 1.45 (,s, 3H,CH₃), 1.89 (d, J=1.2 Hz, 3H, 2-CH₃), 3.63 (t, J=8.0 Hz, 1H, H-5),4.14-4.23 (m, 3H, H-5′ and —OCH₂ CH₃), 4.86 (dd, J=7.6 and 13.6 Hz, 1H,H-4), 6.69 (dd, J=1.6 and 8.0 Hz, 1H, H-3),

Example 2(2S,3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionicacid ethyl ester (42)

A round-bottomed flask, equipped with a magnetic stirrer, is chargedwith 25 mL of t-BuOH, 25 mL of water, and 7.0 g of AD-mix-β. Stirring atroom temperature produced two clear phases; the lower aqueous phaseappears bright yellow. Methanesulfonamide (475 mg) is added at thispoint. The mixture is cooled to 0° C. whereupon some of the dissolvedsalts precipitated, 1.07 g (5 mmol) of 41 is added at once, and theheterogeneous slurry is stirred vigorously at 0° C. for 24 h. After thistime, while the mixture is stirred at 0° C., solid sodium sulfite (7.5g) is added and the mixture allowed to warm to room temperature andstirred for 30-60 min. EtOAc (50 mL) is added to the reaction mixture,and after separation of the layers, the aqueous phase is furtherextracted with EtOAc. The organic layer is dried over Na₂SO₄ andconcentrated to dryness. The residue is purified by silica gel columnchromatography with 20% EtOAc in hexanes to provide 42 (1.13 g, 91%) asa solid. ¹H NMR (DMSO-d₆) □ 1.18 (t, J=6.8 Hz, 3H, —OCH₂ CH₃ , 1.24 (,s, 3H, CH₃), 1.25 (, s, 3H, CH₃), 1.28 (s, 3H, 2-CH3), 3.67 (t, J=7.2Hz, 1H), 3.85, 4.06 and 4.12 (m, 4H), 4.96 (s, 1H, 2—OH, D₂Oexchangeable), 5.14 (d, J=7.6 Hz, 2-OH, D₂O exchangeable). Anal. Calcdfor C₁₁H₂₀O₆: C, 53.22; H, 8.12. Found: C, 53.32; H, 8.18.

Example 3(2S,3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-3-benzoyloxy-2-hydroxy-2-methylpropionicacid ethyl ester (43)

To a solution of compound 42 (245 mg, 0.99 mmol) in dry pyridine (3 mL)is added dropwise a solution of BzCl (300 mg, 2.1 mmol) in pyridine (1mL). After the mixture is stirred at room temperature for 2 h, thereaction is quenched with H₂O (1 mL). The mixture is concentrated todryness and the residue is partitioned between CH₂Cl₂ and sat. NaHCO₃solution. The organic phase is dried (anh. Na₂SO₄), filtered andconcentrated. The residue is purified by silica gel columnchromatography with 5% EtOAc in hexanes to give 43 (247 mg, 71%) as asolid. Anal. Calcd for C₁₈H₂₄O₇: C, 61.35; H, 6.86. Found: C, 60.95; H,6.73.

Example 4(2R,3R)-3-[(4R)-2,2-Dimethyl-[1,3]dioxolan-4-yl]-3-benzoyloxy-2-fluoro-2-methyl-propionicacid ethyl ester (44)

To a solution of compound 43 (36 mg, 0.102 mmol) in anhydrous THF (1.5mL) is added DAST or Deoxofluor (0.08 mL, 0.68 mmol) at 0° C. underargon. The reaction mixture is stirred at room temperature for 3 h, thencooled down to 0° C., and carefully treated with cold saturated NaHCO₃solution (2 mL). The organic layer is dried over Na₂SO₄ and concentratedto dryness. The residue is purified by silica gel column chromatographywith 1-3% EtOAc in hexanes to give 44 (24.6 mg, 68%) as a syrup. HR-FABMS; Obsd: m/z 361.1621. Calcd for C₁₈H₂₃O₆FLi: m/z 361.1639 (M+H)⁺.

Example 5 3-O-Benzoyl-2-methyl-2-deoxy-2-fluoro-D-ribono-γ-lactone (45)

A mixture of compound 44 (308 mg, 0.86 mmol), MeCN (20 mL), water (1 mL)and CF₃CO₂H (0.17 mL) is refluxed at 80-85° C. for 3 h. The open-chainintermediate is not isolated, but converted directly to 45 by azeotropicdistillation using a Dean-Stark water separator. The removed MeCN isreplaced with dry toluene, and the azeotropic distillation continueduntil the oil bath temperature reached 130° C. Stirring at 130° C. iscontinued overnight. The mixture is then cooled to room temperature andthe solvent is removed in vacuo to give a syrup, which is purified bysilica gel column chromatography with 10-15% EtOAc in hexanes to give,after solvents evaporation, solid 45 (136 mg, 58.3%).

Example 6 3,5-Di-O-benzoyl-2-methyl-2-deoxy-2-fluoro-D-ribono-γ-lactone(49)

To a solution of 45 (60 mg, 0.224 mmol) in EtOAc (1 mL) are addedpyridine (100 mg, 1.26 mmol) and 4-dimethylaminopyridine (2.7 mg). Themixture is warmed to 60° C. and BzCl (110 mg, 0.79 mmol) in EtOAc (0.4mL) is added dropwise. After stirring for 3 h, the mixture is cooled to0° C. and pyridine HCl salt is filtered off. The filtrate is dilutedwith EtOH and the mixture is evaporated to dryness. The residue ispurified by silica gel column chromatography with 3-6% EtOAc in hexanesto provide, after solvents evaporation, solid 49 (75 mg, 91%).

Example 7 2-Methyl-D-arabino-γ-lactone (46)

A solution of compound 42 (248 mg, 1 mmol) in 1.5 mL of EtOH is treatedwith 0.3 mL of concentrated HCl. The reaction mixture is stirred at roomtemperature for 2 h. The solvent is removed in vacuo (bath temp. <45°C.). The residue is co-evaporated with toluene (3×10 mL) to give aresidue, which is purified by silica gel column chromatography with 70%EtOAc in hexanes. Evaporation of solvents give oily 46 (170 mg, 105%).Anal. Calcd for C₆H₁₀O₅: C, 41.24; H, 6.22. Found: C, 41.00; H, 6.74.

Example 8 3,5-Di-O-benzoyl-2-methyl-D-arabino-γ-lactone (47)

To a stirred solution of compound 46 (880 mg, 5.4 mmol) in dry pyridine(80 mL) is added dropwise a solution of BzCl (1.73 g, 12.29 mmol) in drypyridine (45 mL) at room temperature over a period 75 min. The mixtureis stirred for another 90 min, then treated with MeOH (5 mL), andconcentrated to dryness. The residue is purified by silica gel columnchromatography with 12-20% EtOAc in hexanes to give 47 (1.1 g, 55%) asan oil.

Example 9 3,5-Di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribonolactone(49)

To a solution of 47 (430 mg, 1.16 mmol) in anhydrous THF (20 mL) anddiisopropylethylamine (1 mL, 5.74 mmol) is added DAST or DEOXOFLUOR(0.48 mL, 3.66 mmol) at room temperature under argon. The reactionmixture is stirred at room temperature for 3 h, then cooled down to 0°C., and carefully treated with cold saturated NaHCO₃ solution (5 mL).The reaction mixture is partitioned between EtOAc (100 mL) and water (20mL). The organic layer is dried over (Na₂SO₄) and concentrated todryness. The residue is purified by silica gel column chromatographywith 3-6% EtOAc in hexanes to provide 49 (220 mg, 51%) as a solid.

Example 10 3,5-Di-O-benzoyl-2-methyl-D-ribono-lactone (48)

To a solution of 47 (160 mg, 0.432 mmol) in anhydrous CH₂Cl₂ (5 mL) isadded DAST or DEOXOFLUOR (0.15 mL, 1.14 mmol) at 0-5° C. under argon.The reaction mixture is stirred at 0-5° C. for 1 h then at roomtemperature. After 24 hrs, the reaction still does not go well as thereis no major less polar product appears in the TLCs. The reaction mixtureis cooled to 0° C., and carefully treated with cold saturated NaHCO₃solution. The organic layer is dried over Na₂SO₄ and concentrated todryness. The residue is checked by proton NMR. It shows that the majorproduct is 3,5-dibenzoyl-2-methyl-D-ribono-γ-lactone (48), which isidentical with authentic sample. Traces of 49 are detected on thespectrum.

Example 11 3,5-Di-O-methoxymethyl-2-C-methyl-D-arabino-γ-lactone (50)

To a solution of 2-methylarabinolactone (46) (324 mg, 2 mmol) inCH₂(OMe)₂ (30 mL) and CH₂Cl₂ (30 mL) was added CF₃SO₃H (50 μL), and thesolution was stirred at RT under argon for 14 h. The reaction wasquenched by addition of 28% NH₄OH (0.1 mL), and the mixture was dried byaddition of Na₂SO₄. After removal of the solvent by evaporation, theresidue was purified by flash chromatography on silica gel eluting withCH₂Cl₂/MeOH (95:5 to 9:1) to give 450 mg (90%) of product as a paleyellow oil. ¹H-NMR (DMSO-d₆): 6.10 (s, OH, D₂O exchangeable), 4.70 (q,2H, CH₂), 4.62 (d, 2H, CH₂), 4.30 (m, 1H, H-4), 4.20 (d, 1H, H-3),3.80-3.65 (m, 2H, H-5), 3.30, 3.28 (2s, 6H, 2 CH₃), 1.26 (s, 3H, CH₃).

Example 123,5-Di-O-methoxymethyl-2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ-lactone(51)

To a solution of 50 (100 mg, 0.4 mmol) in CH₂Cl₂ (3 mL) and pyridine(0.5 mL) at −78° C. is added DAST or DEOXOFLUOR (0.21 mL, 1.6 mmol), andthe solution is stirred at −78° C. for 15 min. Then the solution isallowed to warm up to room temperature and stirred at room temperaturefor 2 h. The reaction is quenched by addition of saturated aqueousNaHCO₃ (0.5 mL) and ice-water (0.5 mL), followed by CH₂Cl₂ (20 mL) andsaturated aqueous NaHCO₃ (10 mL). The aqueous layer is extracted withCH₂Cl₂ twice, the combined organic layers are washed with NaHCO₃, anddried over Na₂SO₄. The evaporation of the solvent gives 51 (88 mg, 87%)as a brownish-yellow oil. ¹H-NMR (DMSO-d₆): 4.74 (q, J=6.9 & 18.1 Hz,2H, CH₂), 4.63 (d, J=0.77 Hz, 2H, CH₂), 4.54 (m, 1H, H-4), 4.18 (dd,J=7.8 & 20.0 Hz, 1H, H-3), 3.86-3.71 (m, 2H, H-5), 3.34, 3.28 (2s, 6H, 2CH₃), 1.59 (d, J=24.26 Hz, 3H, CH₃).

Example 13 Ethyl 4,5-O-Isopropylidene-3,4,5-trihydroxy-2-methylvalerate(54)

To activated zinc (6.5 g, 0.10 mmol) is added about 20 mL of a solutioncontaining 39 (13.0 g, 0.1 mmol), 53 (13.0 mL, 0.10 mmol), THF (50 mL),and diethyl ether (50 mL). After the addition, one crystal of 12 isadded, whereby an exotherm is generated, causing the solution to reflux.The remaining solution is added over about 0.75 h as to maintain agentle reflux. The mixture is gently heated to reflux for an additional1 h after the final addition. The mixture is cooled to room temp, pouredinto ice (200 mL) and 1 N HCl (200 mL) and allowed to stir until most ofthe ice had melted (about 0.5 h). The organic layer is separated and theaqueous layer is extracted with diethyl ether (2×75 mL). The combinedorganic layers are washed with satd NaHCO₃ (1×150 mL), brine (1×150 mL),dried (Na₂SO₄), filtered, and concentrated to dryness in vacuo. Furtherdrying in vacuo provides 54 as a mixture of diastereomers (15.1 g,65.1%). This compound is used without further purification.

Example 14 Ethyl 4,5-O-Isopropylidene-3-oxo-2-methylvalerate (55)

Compound 54 (9.85 g, 0.042 mol) is dissolved in dry THF (50 mL).Anhydrous DMSO (16.0 mL, 0.22 mol) is added and the resulting solutionis cooled to between −20° C. and −15° C. Trifluoroacetic anhydride (9.8mL, 0.69 mol) is added dropwise over 15 minutes and the solution isstirred between −20° C. and −15° C. for 2 h after which anhydrous NEt₃(24.0 mL, 0.17 mol) is added over 20 min. The resulting solution isstirred at room temp for 1 h, diluted with diethyl ether (50 mL), andwashed with H₂O (3×100 mL), dried (Na₂SO₄) and concentrate in vacuo tocompound 55 as a yellow oil (8.1 g, 82.0%) that is used without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): δ 1.24-1.38 (m, 26H), 3.81 (q,1.3; H, J=7.3 Hz), 3.89 (q, 1.0H, J=7.3 Hz), 3.99-4.04 (m, 3H),4.10-4.20 (m, 7H), 4.21-4.29 (m, 3H), 4.51 (dd, 1.0H, J=8.1, 6.2 Hz),4.58 (dd, 1.3H, J=7.7, 5.0 Hz).

Example 15 Ethyl 4,5-O-Isopropylidene-2-fluoro-3-keto-2-methylvalerate(56)

Compound 55 (7.36 g, 0.042 mol) is dissolved in anhydrous DMF (5.0 mL)and treated with a slurry of Selectfluor (55.0 g, 0.155 mol) in DMF(45.0 mL). The mixture is placed in an oil bath maintained at 45-50° C.and the suspension is maintained with stirring at that temperatureovernight under an argon atmosphere. The solution is concentrated tonear dryness in vacuo, treated with diethyl ether (˜25 mL) and washedwith water (3×100 mL). The organic phase is dried (Na₂SO₄) andconcentrate in vacuo to compound 56 as a yellow oil (5.65 g, 71.2%) thatwas an approximate 1:1 mixture of 2R:2S fluorinated compound as judgedby ¹⁹F NMR. ¹H NMR (CDCl₃, 400 MHz): δ 1.20-1.46 (m, 16H), 1.70 (2d, 3H,J=22.8 Hz), 4.05-4.10 (m, 2H,), 4.12-4.32 (m, 2H,), 4.90-97 (m, 1H). ¹⁹FNMR (CDCl₃, 376 MHz, C₆F₆ external standard): δ 4.30 (q), 4.01 (q).

Example 16 3,5-O-dipivaloyl-2-methyl-D-arabino-γ-lactone (47 B)

To a solution of 42 (4 mmol, 897 mg) in EtOH (20 mL) was addedconcentrated HCl (2.0 mL), and the solution stirred at room temperaturefor 1 h. The solution was concentrated to dryness and the residue wasco-evaporated with THF (10 mL) and dissolved in pyridine (6 mL) andCH₂Cl₂ (14 mL). The solution was cooled in ice-bath. To the solution wasadded pivaloyl chloride (8 mmol, 0.98 mL) and the solution stirred at 0°C. for 30 min. To the solution was added an additional pivaloyl chloride(4 mmol, 0.49 mL) and the solution stirred at room temperature for 5 h.To the solution was added 4-dimethylaminopyridine (100 mg) and thesolution was stirred at room temperature for 20 h. H₂O (5 mL) was addedand the mixture was stirred at room temperature for 20 min. EtOAc (50mL) was added. The mixture was washed with water, brine and dried(Na₂SO₄). Solvent was removed and the residue was recrystallized fromEtOAc-Hexanes to give fine crystals (625 mg, 47%). H-NMR (CDCl₃): δ 5.18(d, J=6.80 Hz, 1H, H-3), 4.45, 4.22 (m, 2H, H-5), 4.41 (m, 1H, H-4),3.32 (br s, 1H, OH, D2O exchangeable), 1.43 (s, 1H, Me), 1.25, 1.22 [ss,18H, C(Me)₃].

Example 172-Deoxy-3,5-O-dipivaloyl-2-fluoro-2-C-methyl-D-ribono-γ-lactone (49B)

To a solution of 47B (100 mg, 0.3 mmol) in THF (5 mL) were added EtNPr₂(2 mmol, 0.35 mL) and Deoxo-Fluor (0.18 mL, 0.9 mmol), and the solutionwas stirred at room temperature for 4 h. To the solution was addedadditional Deoxo-Fluor (0.18 mL, 0.9 mmol) and the solution was stirredat room temperature for 16 h, refluxed for 1 h. EtOAc (50 mL) was added.The solution was washed with aqueous NaHCO₃, brine, dried (Na₂SO₄).Solvent was removed and the residue was purified by column (10% EtOAc inhexanes) to give product as a solid (65 mg, 65%). H-NMR (CDCl₃): δ 5.12(m, 1H, H-3), 4.68 (m, 1H, H-4), 4.41, 4.18 (mm, 2H, H-5), 1.63 (d,J=23.2Hz, 1H, Me), 1.25, 1.20 [ss, 18H, C(Me)₃].

1. A compound of the following formula:

wherein R³ and R⁵ can be independently H, CH₃, benzyl, 4-methoxybenzyl,trityl, trialkylsilyl, t-butyldialkylsilyl, t-butyldiphenylsilyl,tetraisopropyldisilyl (TIPDS), tetrahydropyranyl (THP), methoxymethyl(MOM), β-methoxyethoxymethyl (MEM), or acyl; alternatively, R³ and R⁵are linked through —SiR₂—O—SiR₂— or —SiR₂—, wherein R is a lower alkyl.2. A compound of claim 1, wherein R³ and R⁵ are each independently H,CH₃, acetyl, benzoyl, pivaloyl, 4-nitrobenzoyl, 3-nitrobenzoyl,2-nitrobenzoyl, 4-chlorobenzoyl, 3-chlorobenzoyl, 2-chlorobenzoyl,4-methylbenzoyl, 3-methylbenzoyl, 2-methylbenzoyl, 4-phenylbenzoyl,benzyl, 4-methoxybenzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl,t-butyldiphenylsilyl, TIPDS, THP, MOM, or MEM.
 3. A compound of claim 1,wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzoyl,benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl,t-butyldiphenylsilyl, TIPDS, THP, MOM, or MEM.
 4. A compound of claim 1,wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzyl, trityl,trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, orTHP.
 5. A compound of claim 1, wherein R³ and R⁵ are each independentlyH, CH₃, acetyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl,t-butyldiphenylsilyl, or TIPDS.
 6. A compound of claim 1, wherein R³ andR⁵ are each independently H, CH₃, acetyl, benzyl, trialkylsilyl,t-butyl-dialkylsilyl, t-butyldiphenylsilyl, or TIPDS.
 7. A compound ofclaim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, orbenzyl.
 8. A compound of claim 1, wherein R³ and R⁵ are eachindependently H, CH₃, or acetyl.
 9. A compound of claim 1, wherein R³and R⁵ are each independently H or CH₃.
 10. A compound of claim 1,wherein R³ and R⁵ are H.
 11. A compound of claim 1, wherein R³ and R⁵are CH₃.
 12. A compound of claim 1, wherein R³ and R⁵ are acetyl.
 13. Acompound of claim 1, wherein R³ and R⁵ are benzyl.
 14. A compound ofclaim 1, wherein R³ and R⁵ are acyl.
 15. A compound of claim 1, whereinR³ and R⁵ are linked through —SiR₂—O—SiR₂— or —SiR₂—, and wherein R isselected from among methyl, ethyl, n-propyl, and i-propyl.
 16. A processfor the preparation of the compound of claim 1 wherein R⁵ is H and R³ isBz, comprising the steps of: (a) reacting a compound of the formula, 39,

with an alkyl-2-bromopropionate in the presence of activated zinc in asolvent; (b) adding an oxidizing agent to provide a ketone; (c)fluorinating the product of step (b) to produce a fluorinated ketone;(d) reducing the fluorinated ketone of step (c); and (e) benzylating theproduct of step (d).
 17. The process of claim 16, wherein the solvent ofstep (a) is selected from the group consisting of diethyl ether andtetrahydrofuran.
 18. The process of claim 16, wherein the oxidizingagent of step (b) is selected from the group consisting of: an activateddimethylsulfoxide, a chromatic agent, a Dess-Martin periodione, andtetrapropylammonium perruthenate.